scholarly journals High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not Adults

2018 ◽  
Vol 9 ◽  
Author(s):  
Julia Roider ◽  
Takashi Maehara ◽  
Abigail Ngoepe ◽  
Duran Ramsuran ◽  
Maximilian Muenchhoff ◽  
...  
Keyword(s):  
High Frequency ◽  
Germinal Centers ◽  
Regulatory Cells ◽  
Follicular Helper

scholarly journals A distinct subpopulation of CD25− T-follicular regulatory cells localizes in the germinal centers

2017 ◽  
Vol 114 (31) ◽  
pp. E6400-E6409 ◽  
Author(s):  
James Badger Wing ◽  
Yohko Kitagawa ◽  
Michela Locci ◽  
Hannah Hume ◽  
Christopher Tay ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Germinal Center ◽  
Germinal Centers ◽  
Regulatory Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Distinct Subpopulation ◽  
Wide Range ◽  
Multistep Process

T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.

scholarly journals THU0231 IL-2 DRIVES THE CONVERSION OF T FOLLICULAR HELPER TO T FOLLICULAR REGULATORY CELLS THROUGH EPIGENETIC MODIFICATION IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 343.2-343
Author(s):  
H. Hao ◽  
S. Nakayamada ◽  
Y. Kaoru ◽  
N. Ohkubo ◽  
S. Iwata ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Flow Cytometry ◽  
B Cells ◽  
Histone Modifications ◽  
Lupus Erythematosus ◽  
Regulatory Cells ◽  
Systemic Lupus ◽  
Research Support ◽  
Tfh Cells ◽  
Follicular Helper

Background:Systemic lupus erythematosus (SLE) is a complex polygenic autoimmune disease characterized by immune-system aberrations. Among several types of immune cells, T follicular helper (Tfh) cells promote autoantibody production, whereas T follicular regulatory (Tfr) cells suppress Tfh-mediated antibody responses.(1)Objectives:To identify the characteristics of Tfr cells and to elucidate the mechanisms of conversion of Tfh cells to Tfr cells, we probed the phenotype of T helper cells in patients with SLE and underlying epigenetic modifications by cytokine-induced signal transducer and activators of transcription (STAT) family factors.Methods:Peripheral blood mononuclear cells from SLE patients (n=44) and healthy donors (HD; n=26) were analyzed by flow cytometry. Memory Tfh cells were sorted and cultured under stimulation with T cell receptor and various cytokines. Expression of characteristic markers and phosphorylation of STATs (p-STATs) were analyzed by flow cytometry and quantitation PCR. Histone modifications were evaluated by chromatin immunoprecipitation.Results:The proportion of CXCR5+FoxP3+Tfr cells in CD4+T cells tended to increase (2.1% vs 1.7%, p=0.17); however, that of CD4+CD45RA-FoxP3hiactivated Tfr cells in Tfr cells was decreased (4.8% vs 7.1%, p<0.05), while CD4+CD45RA-FoxP3lownon-suppressive Tfr cells was increased (50.1% vs 38.2%, p<0.01) in SLE compared to HD. The percentage of PD-1hiactivated Tfh cells was significantly higher in SLE compared to HD (15.7% vs 5.9%, p<0.01). Furthermore, active patients had a higher ratio of activated Tfh/Tfr cells compared to inactive patients. In vitro study showed that IL-2, but not other cytokines such as TGF-β1, IL-12, IL-27, and IL-35, induced the conversion of memory Tfh cells to functional Tfr cells characterized by CXCR5+Bcl6+Foxp3hipSTAT3+pSTAT5+cells. The loci ofFOXP3at STAT binding sites were marked by bivalent histone modifications. After IL-2 stimulation, STAT5 directly bound on FOXP3 gene loci accompanied by suppressing H3K27me3. Finally, we found that serum level of IL-2 was decreased in SLE and that stimulation with IL-2 suppressed the generation of CD38+CD27+B cells by ex vivo coculture assay using Tfh cells and B cells isolated from human blood.Conclusion:Our findings indicated that the regulatory function of Tfr cells is impaired due to the low ability of IL-2 production and that IL-2 restores the function of Tfr cells through conversion of Tfh cells to Tfr cells in SLE. Thus, the reinstatement of the balance between Tfh and Tfr cells will provide important therapeutic approaches for SLE.References:[1]Deng J, Wei Y, Fonseca VR, et al. T follicular helper cells and T follicular regulatory cells in rheumatic diseases. Nat Rev Rheumatol. 2019; 15 (8): 475-90.Disclosure of Interests: :He Hao: None declared, Shingo Nakayamada Grant/research support from: Mitsubishi-Tanabe, Takeda, Novartis and MSD, Speakers bureau: Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei and Pfizer, Yamagata Kaoru: None declared, Naoaki Ohkubo: None declared, Shigeru Iwata: None declared, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin

scholarly journals Nanoparticle-mediated delivery of IL-2 to T follicular helper cells protects BDF1 mice from lupus-like disease

2021 ◽  
Vol 2 (3) ◽  
pp. 185-193
Author(s):  
Concetta Ferretti ◽  
David A. Horwitz ◽  
Sean Bickerton ◽  
Antonio La Cava
Keyword(s):  
T Cells ◽  
Lupus Erythematosus ◽  
Low Dose ◽  
T Regulatory Cells ◽  
Plga Nanoparticles ◽  
Regulatory Cells ◽  
Beneficial Effects ◽  
Follicular Helper ◽  
New Strategy ◽  
Extended Survival

Abstract We recently reported that poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with interleukin (IL)-2 and targeted to T cells inhibited the development of lupus-like disease in BDF1 mice by inducing functional T regulatory cells (Tregs). Here we show that the protection from disease and the extended survival of BDF1 mice provided by IL-2-loaded NPs targeted to T cells is not only due to an induction of Tregs but also contributed by an inhibition of T follicular helper (TFH) cells. These results identify a dual protective activity of IL-2 in the control of lupus autoimmunity, namely the inhibition of effector TFH cells, in addition to the previously known induction of Tregs. This newly recognized activity of IL-2 delivered by NPs can help better explain the beneficial effects of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE), and might be considered as a new strategy to slow disease progression and improve outcomes in lupus patients.

scholarly journals IL-10–producing Tfh cells accumulate with age and link inflammation with age-related immune suppression

2020 ◽  
Vol 6 (31) ◽  
pp. eabb0806 ◽  
Author(s):  
Maha Almanan ◽  
Jana Raynor ◽  
Ireti Ogunsulire ◽  
Anna Malyshkina ◽  
Shibabrata Mukherjee ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Suppression ◽  
Serum Levels ◽  
Normal Serum ◽  
Antibody Responses ◽  
Regulatory Cells ◽  
Aged Mice ◽  
Follicular Helper ◽  
Forkhead Box ◽  
Age Related

Aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system. In addition to increased interleukin-6 (IL-6), we found aged mice exhibit increased systemic IL-10 that requires forkhead box P3–negative (FoxP3−), but not FoxP3+, CD4+T cells. Most IL-10–producing cells manifested a T follicular helper (Tfh) phenotype and required the Tfh cytokines IL-6 and IL-21 for their accrual, so we refer to them as Tfh10 cells. IL-21 was also required to maintain normal serum levels of IL-6 and IL-10. Notably, antigen-specific Tfh10 cells arose after immunization of aged mice, and neutralization of IL-10 receptor signaling significantly restored Tfh-dependent antibody responses, whereas depletion of FoxP3+ regulatory and follicular regulatory cells did not. Thus, these data demonstrate that immune suppression with age is reversible and implicate Tfh10 cells as an intriguing link between “inflammaging” and impaired immune responses with age.

scholarly journals Landscape of T Follicular Helper Cell Dynamics in Human Germinal Centers

2020 ◽  
Vol 205 (5) ◽  
pp. 1248-1255
Author(s):  
Emmanuel Donnadieu ◽  
Kerstin Bianca Reisinger ◽  
Sonja Scharf ◽  
Yvonne Michel ◽  
Julia Bein ◽  
...  
Keyword(s):  
Germinal Centers ◽  
Helper Cell ◽  
Cell Dynamics ◽  
Follicular Helper ◽  
T Follicular Helper Cell
Sign in / Sign up

Export Citation Format

Share Document